Mechanistic significance of a novel molecular target in the FOXO signaling pathwa

FOXO 信号通路中新分子靶点的机制意义

• 批准号: 8748694
• 负责人: Usha N. Kasid
• 金额: $ 7.78万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8748694
• 关键词: Adjuvant Therapy; Affinity Chromatography; African American; Apoptotic; BRCA1 Mutation; Binding Sites; Biological Assay; Breast; Breast Cancer Cell; Cancer Cell Growth; Cancer Patient; Cell Death; Cells; ChIP-seq; Chemosensitization; Clinical; Combination Drug Therapy; Complementary DNA; Cytotoxic Chemotherapy; DNA; DNA Binding; Data; Disease; Distant Metastasis; Dose; Drug resistance; ERBB2 gene; Future; Genes; Helper-Inducer T-Lymphocyte; Infection; Knowledge; Lead; Link; MCF7 cell; MDA MB 231; MLLT7 gene; Mass Spectrum Analysis; Mediating; MicroRNAs; Molecular Target; Neoplasm Metastasis; Oligoribonucleotides; Outcome; Outcomes Research; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Procedures; Prognostic Factor; Protein Binding; Proteins; Quantitative Reverse Transcriptase PCR; Relapse; Relative (related person); Reporter; Research; Research Project Grants; Research Proposals; Reverse Transcription; Role; Signal Pathway; Signal Transduction; Specimen; Systems Biology; Testing; Time; Toxic effect; Transcriptional Regulation; Transfection; Tumor Suppressor Proteins; Validation; Variant; Woman; Work; base; cancer cell; chemotherapy; cytotoxic; cytotoxicity; drug sensitivity; improved; mRNA Expression; malignant breast neoplasm; member; mortality; mutant; mutation carrier; nanotherapeutic; neuroblastoma cell; novel; outcome forecast; overexpression; promoter; prospective; public health relevance; response; small hairpin RNA; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor progression

DESCRIPTION (provided by applicant): The triple negative breast cancer (TNBC) is an aggressive form of breast cancer frequently seen in African American women and BRCA1 mutation carriers. The TNBC tumors often relapse with distant metastases following standard cytotoxic chemotherapy. The overarching research objective of this small research application is to elucidate a new mechanism of chemosensitivity of breast cancer. While some apoptotic molecules do enhance cytotoxic effects of chemotherapeutic drugs, to date none of these molecules is a clinically robust target in advanced breast cancer. To this end, we have demonstrated that BLID, BH-3 Like motif containing Inducer of cell Death, is a strong prognostic factor in invasive breast cancer. Recently, BLID expression has been shown to inhibit breast cancer cell growth and metastasis. In addition, BLID mRNA expression is significantly reduced in certain grade 3 relative to grade 1 and grade 2 breast cancers, suggesting a potential role of transcriptional regulation of BLID in breast cancer progression. Despite the fact that members of the Forkhead boxO (FOXO) subfamily of transcriptional regulators have been linked with breast pathogenesis and prognosis, their mechanisms of action in breast cancer are largely unknown. Therefore, approaches that explain and target such mechanisms could offer important clues to safe and effective ways of managing breast cancer. In preliminary studies, BLID seems to be a likely effector of FOXO3a, and expression of BLID cDNA nanotherapeutic increases chemosensitivity in breast cancer cells. Furthermore, microRNAs miR-21, miR-155 and miR-34a may be components of the FOXO/BLID signaling pathway. The specific research aims are: 1) To demonstrate a novel FOXO-BLID signaling pathway and BLID-mediated chemosensitivity in breast cancer cells using DNA affinity purification and mass spectrometry, and the ChIP-Seq strategy. 2) To examine the integrative roles of BLID and microRNAs in chemosensitization of TNBC cells. Successful outcomes of this research will provide the basis for future studies of a comprehensive analysis of the FOXO-BLID signaling pathway that may explain why certain breast cancers fail chemotherapies. This work will also establish the first functional link between BLID and three prominent microRNAs, and may lead to a prospective validation of the microRNA module(s) in clinical TNBC specimens. Building on this project, a new systems biology approach involving FOXO/BLID-centric gene networks and circulating microRNAs could be developed. This information will be unique and significant since very little is known about the systems biology of TNBC cell death and drug sensitivity or resistance.

描述（由申请人提供）：三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，常见于非裔美国妇女和BRCA 1突变携带者。TNBC肿瘤通常在标准细胞毒性化疗后复发并伴有远处转移。这个小型研究应用的总体研究目标是阐明乳腺癌化疗敏感性的新机制。虽然一些凋亡分子确实增强了化疗药物的细胞毒性作用，但迄今为止，这些分子都不是晚期乳腺癌的临床稳健靶点。为此，我们已经证明BLID，BH-3样基序含有细胞死亡诱导物，是浸润性乳腺癌的强预后因子。最近，BLID表达已显示出抑制乳腺癌细胞生长和转移。此外，BLID mRNA表达在某些3级乳腺癌中相对于1级和2级乳腺癌显著降低，表明BLID的转录调控在乳腺癌进展中的潜在作用。尽管转录调节因子的叉头盒O（FOXO）亚家族的成员与乳腺发病机制和预后有关，但它们在乳腺癌中的作用机制在很大程度上是未知的。因此，解释和靶向这些机制的方法可以为安全有效地管理乳腺癌提供重要线索。在初步研究中，BLID似乎是FOXO 3a的可能效应物，并且BLID cDNA纳米管的表达增加乳腺癌细胞中的化学敏感性。此外，microRNA miR-21、miR-155和miR-34 a可能是FOXO/BLID信号通路的组分。具体的研究目的是：1）使用DNA亲和纯化和质谱，以及ChIP-Seq策略，证明乳腺癌细胞中新的FOXO-BLID信号通路和BLID介导的化疗敏感性。2)研究BLID和microRNA在TNBC细胞化学增敏中的整合作用。这项研究的成功结果将为未来对FOXO-BLID信号通路的全面分析提供基础，这可能解释为什么某些乳腺癌化疗失败。这项工作还将建立第一个职能联系， BLID和三种突出的microRNA，并可能导致临床TNBC标本中microRNA模块的前瞻性验证。在这个项目的基础上，可以开发一种新的系统生物学方法，包括FOXO/BLID中心基因网络和循环microRNA。这些信息将是独特和重要的，因为对TNBC细胞死亡和药物敏感性或耐药性的系统生物学知之甚少。